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The CUL4B-miR-372/373-PIK3CA-AKT axis regulates metastasis in bladder cancer.
Oncogene ( IF 6.634 ) Pub Date : 2020-03-03 , DOI: 10.1038/s41388-020-1236-1
Xiaochen Liu,Jianfeng Cui,Li Gong,Fei Tian,Yangli Shen,Lipeng Chen,Yong Wang,Yangyang Xia,Lei Liu,Xiang Ye,Molin Wang,Guangyi Liu,Baichun Jiang,Changshun Shao,Yongxin Zou,Yaoqin Gong

CUL4B, which acts as a scaffold protein in CUL4B-RING ubiquitin ligase (CRL4B) complexes, participates in a variety of biological processes. Previous studies have shown that CUL4B is often overexpressed and exhibits oncogenic activities in a variety of solid tumors. However, the roles and the underlying mechanisms of CUL4B in bladder cancer (BC) were poorly understood. Here, we showed that CUL4B levels were overexpressed and positively correlated with the malignancy of BC, and CUL4B could confer BC cells increased motility, invasiveness, stemness, and chemoresistance. The PIK3CA/AKT pathway was identified as a critical downstream mediator of CUL4B-driven oncogenicity in BC cells. Furthermore, we demonstrated that CRL4B epigenetically repressed the transcription of miR-372/373, via catalyzing monoubiquitination of H2AK119 at the gene cluster encoding miR-372/373, leading to upregulation of PIK3CA and activation of AKT. Our findings thus establish a critical role for the CUL4B-miR-372/373-PIK3CA/AKT axis in the pathogenesis of BC and have important prognostic and therapeutic implications in BC.
更新日期:2020-03-03

 

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